Prescription Opioids An Introduction and Overview of An Introduction and Overview of Pharmacology and Effects Michael Palladini, RPh MBA CADC Michael Palladini, RPh MBA CADC Webinar and online course are co sponsored by the Pennsylvania Certification Board (PCB) Pennsylvania Certification Board (PCB)
Learning Objectives: Learning Objectives: Identify the various opioid medications p prescribed and their pharmacological differences p g and similarities. Understand the neurochemical affects of opioids on the brain and the resulting symptoms. Understand the use of opioid medications in the t t treatment of opiate dependency, and the t f i t d d d th neurochemical and pharmacological principles at work. work
2009 DAWN Report 2009 DAWN Report In 2009, 1.2 million ED visits involved the, nonmedical use of pharmaceuticals or dietary supplements. The most frequently reported drugs in the nonmedical use category of ED visits were in the nonmedical use category of ED visits were opiate/opioid analgesics, present in 50 percent of nonmedical use ED visits hydrocodone (alone or in combination) in 104,490 ED visits oxycodone (alone or in combination) in 175,949 oxycodone (alone or in combination) in 175 949 ED visits methadone in 70,637 ED visits.,
$ Workplace insurers spend an estimated $1.4 billion annually on narcotic painkillers, or opioids. Sales of painkillers reached about $8.5 billion last year, compared with $4.4 billion in 2001, according to the consulting firm IMS Health. Between 2001 and 2008, narcotics prescriptions p p as a share of all drugs used to g treat workplace injuries jumped 63 percent
2009/2010 Most Prescribed Drugs 2009/2010 Most Prescribed Drugs #1 #1 Hydrocodone/acetaminophen Hydrocodone/acetaminophen 128.2 million prescriptions (2009) 131.2 million prescriptions (2010) 3 2 illi i i (20 0) Average monthly cost of $12 Immediate release formulation Apap Apap use dangerous/questioned use dangerous/questioned
DEA Factsheet DEA Factsheet In 2009, there were 7 million Americans aged 12 years and older who abused prescription drugs for non medical purposes within the past month, up from 6.2 million in 2008. This represents a 13 percent increase in just one year increase in just one year. In 2009, on average, 6,027 persons per day abused prescription pain relievers for the first time. The total number of individuals that initiated drug use with prescription drugs exceeds the number of individuals that initiated drug use with marijuana. that initiated drug use with marijuana. Every day, on average, 2,500 teens use prescription drugs to get high for the first time. 1 in 7 teens admit to abusing prescription drugs to get high in the past year. Sixty percent of teens who abused prescription pain relievers did so before the age of 15. Fifty six six percent of teens believe that prescription drugs are easier to get than illicit drugs. percent of teens believe that prescription drugs are easier to get than illicit drugs. Fifty 2 in 5 teens believe that prescription drugs are much safer than illegal drugs. And 3 in 10 teens believe that prescription pain relievers are not addictive. Sixty three percent of teens believe that prescription drugs are easy to get from friends and family s medicine cabinet. According to the Center for Disease Control, prescription drugs, including opioids and antidepressants, are responsible for more overdose deaths than street drugs such as cocaine, heroin, and amphetamines. The number of emergency room visits attributable to pharmaceuticals alone is up 97% between 2004 and 2008 The number of persons seeking treatment for pain reliever abuse is up more than fourfold between 1998 and 2008
Chemical Puzzle Pieces of the puzzle include: opioids neurotransmitters: dopamine GABA serotonin p endorphins
O i Opium Poppy Contains: Numerous alkaloids, (naturally occurring chemicals), notably: y MORPHINE 10 15% CODEINE 1 3% THEBAINE 1 2% THEBAINE 1 2%
O i Raw Opium Can be smoked in raw form, or processed into morphine, codeine, heroin or other heroin or other chemicals for p pharmaceutical use.
In September, the United Nations Office on Drugs and Crime said the value of Afghan opium rose from $29 per pound in 2009 to the value of Afghan opium rose from $29 per pound in 2009 to $77 per pound last year
REVIEW OF OPIATES REVIEW OF OPIATES NATURAL Morphine Codeine C d i SEMI SYNTHETIC Diacetylmorphine Hydromorphone y p Oxycodone Oxymorphone Hydrocodone Buprenorphine SYNTHETIC Meperidine Fentanyll Methadone
Natural Opiates Natural Opiates Morphine Morpheus 10 15% 10 15% Discovered in 1803 Moderate/severe pain Moderate/severe pain MS Contin, Kadian, Avinza Oramorph Avinza, Oramorph Codeine Poppy Head 1 3% 1 3% Discovered in 1832 Mild/moderate pain Mild/moderate pain, Cough Tylenol with Codeine Tylenol with Codeine
Semi synthetic Semi synthetic Opiates Opiates Diacetylmorphine (Heroin) Diacetylmorphine (Heroin) Hydromorphone (Dilaudid) O Oxycodone (Oxycontin, Roxicodone) d (O i i d ) Oxymorphone (Opana) Hydrocodone (Vicodin, Lortab) Buprenorphine Buprenorphine (Suboxone, Subutex) (Suboxone Subutex)
Synthetic Opiates Synthetic Opiates Meperidine Meperidine Fentanyl Methadone Tramadol * (Demerol) (Duragesic) (Dolophine) (Ultram) Chemical structures are not related to morphine or codeine. *Tramadol considered a non typical opioid.
Opioid Chemistry Opioid Chemistry Different Different chemical structure lends to: chemical structure lends to: Varying degrees of absorption outside and inside of the CNS inside of the CNS. Varying rates of absorption Varying onset and duration of action Varying receptor affinity y g p ff y Varying degree of side effects
Opiate Chemistry Morphine molecule Codeine molecule h l l d l l
Semi synthetic Semi synthetic Opiates Opiates Morphine Oxymorphone Diacetylmorphine Diacetylmorphine Hydromorphone
Semi synthetic Semi synthetic Opiates Opiates Codeine Oxycodone Hydrocodone
Semi synthetic Semi synthetic Opiates Opiates Thebaine Buprenorphine
Relative Strengths ( (Analgesic Potency) l ) Morphine p Codeine Hydrocodone Oxycodone Hydromorphone Oxymorphone Buprenorphine M h d Methadone Fentanyl 1.0 0.5 (metabolism) 0.6 (metabolism) 2.0 7 11 7.0 40 75 7.5 50 100
Morphine Moderate to severe pain relief i li f Active and available for oral and IV for oral and IV administration. IR active in 30 min. ER active in 90 min. Moderate bioavailability (40%) bioavailability (40%) Histamine release and nausea/vomiting
Codeine Mild to moderate pain relief, cough pain relief cough suppression Active only orally IR active in 30 min. No long acting product Moderate Moderate bioavailability (50%) Histamine release and nausea/vomiting Manufactured in combination with APAP
Diacetylmorphine Low oral bioavailability, better through better through insufflation, best absorption IV Metabolizes to M b li morphine once in the CNS Provides rush by entering brain very quickly. Large amount of histamine release with IV
H d d Hydrocodone Mild to moderate pain relief Active only orally IR active in 30 min. No long acting product Good bioavailability (70%) Manufactured in combination with APAP
O d Oxycodone Moderate to severe pain relief pain relief Active only orally IR (Roxicodone) ER (Oxycontin) Very good bioavailability (80+%) bioavailability (80+%) Manufactured alone or in combination with APAP (P APAP (Percocet) t) Multiple receptor site activity
Hydromorphone Severe pain relief Active orally and IV, A ti ll d IV IM (highly water soluble) Highly reactive with mu receptor IR IR products, ER products, ER products newer Good bioavailability, excellent penetration excellent penetration in the Blood Brain Barrier
Oxymorphone Severe pain relief Available as orally active products in IR (generics) IR (generics) ER (Opana) Highly reactive with g y the mu receptor Resistant to several metabolic processes, t b li provides extended action.
Buprenorphine Moderate to severe pain relief, opiate i li f i t dependence treatment High lipid solubility High lipid solubility Partial agonist/antagonist activity i i Long acting drug due to affinity at receptor to affinity at receptor sites
Fentanyl Severe pain relief Fully synthetic Most potent opioid available Highly lipophilic (excellent penetration of the Blood Brain Barrier) Fast acting, short Fast acting short duration chemistry
Methadone Moderate to severe pain relief opiate pain relief, opiate dependence treatment Fully synthetic High but variable bioavailability (40 to 100%) Variable metabolism High tissue binding Enzyme induction E i d ti Long T ½ compared to activity
Meperidine Moderate to severe pain relief i li f First synthetic opiate Weak mu receptor Weak mu receptor activity Antispasmodic activity Neurotoxic concerns Rapid onset of action R id t f ti
d l Tramadol Atypical opioid, chemical analogue of chemical analogue of codeine Available as IR and ER f formulation l i Metabolite has much greater affinity and selectivity for mu receptor High oral oral High bioavailability Noncontrolled substance
Opioid Pharmacology Opioid Pharmacology Pharmacology Pharmacology helps to explain the effects and helps to explain the effects and symptoms produced by drugs in the body. (Indications, side effects, tolerance, (Indications, side effects, tolerance, withdrawal) Pharmacokinetics involves study of the Pharmacokinetics involves study of the processes of absorption, distribution, metabolism and elimination. (Half life, onset of action, duration of action, route of administration)
Opioid Pharmacokinetics Opioid Pharmacokinetics Onset of action is Onset of action is Immediate by IV route Rapid by IM and PO route Rapid by IM and PO route Peak action occurs in 15 minutes to 2 hours, d depending on drug and route di d d t Duration of action is from 2 to 8 hours
ER, XR, SR, TR ER, XR, SR, TR
Opioid Neurochemistry Opioid Neurochemistry Brain structure Brain structure Neuron structure Electrical transmission l i l i i Chemical signaling Neurotransmitters
Opioid Effects Opioid Effects Analgesia Euphoria Sedation N Nausea/Vomiting/Constipation /V iti /C ti ti Depress Cough Reflex Effects on Mood and Reward Effects on Mood and Reward Endocrine Effects Respiratory depression Pruritis Miosis
Neurochemistry Discovery Discovery of mu receptor and endorphins of mu receptor and endorphins Subsequent discovery of delta and kappa receptors Mu receptor Delta receptor Kappa receptor Mu 1 Analgesia Mu 1 Analgesia Analgesia, sedation, Analgesia sedation miosis, respiratory depression, euphoria, dysphoria Mu 2 Sedation, vomiting, respiratory depression, pruritis, euphoria, urinary retention, dependence
Neurotransmitters Gamma aminobutyric acid (GABA).inhibitory Gamma aminobutyric acid (GABA) inhibitory Dopamine.pleasure, reward, memory Endorphins pain relief Endorphins.pain relief Glutamate.pain transmission Substance P.pain transmission, vomiting center Serotonin.pain pathway Norepinephrine.pain pathway
Areas of Brain Areas of Brain Mesolimbic Pathway Pathway Reward Reward Pathway Pathway Includes the VTA (ventral tegmental area, amygdala hippocampus nucleus accumbens amygdala, hippocampus, nucleus accumbens, prefrontal cortex. DA, NE, 5 HT in high concentrations DA NE 5 HT i hi h i Memory, reward, judgment, sensations, movement, coordination p Complex interaction of NTs
Receptor Site Evolution l
Opioid Receptor Activity Opioid Receptor Activity Agonist Antagonist Partial agonist i l i Affinity: Strength of the interaction between g p drug and receptor Efficacy: Measure of the strength of activity or effect from interaction effect from interaction
Opioid Agonists Opioid Agonists Most Most opiates are agonists, stimulating the mu, opiates are agonists stimulating the mu delta and kappa receptors. Relative affinity and genetic differences in Relative affinity and genetic differences in receptor sensitivity account for varying activity. activity High affinity and efficacy
Opioid Partial Agonists Opioid Partial Agonists High High affinity affinity and low efficacy at the mu and low efficacy at the mu receptor. Diminished activity of other opiates. High kappa receptor antagonist activity for High kappa receptor antagonist activity for analgesia and abuse deterrence. High kappa receptor activity leads to ceiling Hi h k i i l d ili effect of analgesia and certain side effects. Buprenorphine
Opioid Antagonists Opioid Antagonists High High affinity affinity and no efficacy at the mu, kappa and no efficacy at the mu kappa and delta receptors. Diminished activity of other opiates other opiates. Oral (naltrexone) and parenteral (naloxone) uses. uses Combined with other opiates (b (buprenorphine:naloxone) hi l )
Opioid Metabolism Opioid Metabolism Liver enzymes account for metabolic breakdown iver en ymes account for metabolic breakdown of substances Thousands of different enzymes have been y identified Huge variation in individuals (genetics, gender, age, diet, disease state, drug interactions) Opioid metabolism results in the production of b th i ti both inactive and active metabolites. In fact, d ti t b lit I f t active metabolites may be more potent than the parent compound parent compound.
Treatment Implications Treatment Implications Tolerance and Dependence and Dependence Detoxification Sh Short Term Withdrawal i hd l Long Term Withdrawal Medication Maintenance Therapy Drug Free Possibilities Drug Free Possibilities
Back to the Mesolimbic Brain Back to the Mesolimbic
Neurochemistry of Addiction Neurochemistry of Addiction In In the absence of pain, reward processes are the absence of pain reward processes are continuously activated by opioids VTA stimulation by opioids increases VTA stimulation by opioids increases Dopamine release from the Nucleus Accumbens Memory circuits are stimulated also, causing associations to form i i f
Opioid Tolerance Opioid Tolerance Mu Mu receptors become less responsive receptors become less responsive Receptors become less available (down regulation) NMDA receptor antagonists and glutamate Involvement with the Locus coeruleus (LC) part of the brain, and norepinephrine output Impact of opioids is offset over time by adjusting mechanisms of neurons j g
Locus Coeruleus/NE Locus Coeruleus/NE Normal Opioid Induced Opioid Removed Moderate levels of NE Reduced levels of NE Excessive levels of NE Wakefulness Drowsiness Anxiety/Wakefulness Breathing Reduced Respiration Increased Respiration Blood Pressure Low Blood Pressure High Blood Pressure
Signs/Symptoms of Acute Opioid Intoxication Constricted pupils Euphoria Apathy Drowsiness Loss of consciousness Loss of consciousness Coma Psychomotor agitation or retardation Decreased respiration Decreased respiration Decreased heart rate Pulmonary edema Impaired social judgment p j g Slurred speech Impaired attention and memory Impaired occupational functioning
Opioid Withdrawal Symptoms Opioid Withdrawal Symptoms Dilated pupils Rhinorrhea Epiphora/lacrimation Piloerection Nausea Vomiting Diarrhea Yawning Muscle cramps Muscle cramps Restlessness Elevated vital signs
Goals of Opioid Replacement Therapy Goals of Opioid Replacement Therapy Detoxification Prevent fatal results Stabilization Address acute withdrawal Maintenance Address long term withdrawal Completion (Drug free) C l ti (D f ) Use of drug taper to minimize withdrawal
Opioid Replacement Therapy Corrective, not Curative Methadone Buprenorphine
Methadone Schedule II Drug Schedule II Drug Treatment use since 1964 Full agonist at the mu receptor Full agonist at the mu receptor Synthetic drug Sl Slow rate of metabolism, highly lipid soluble t f t b li hi hl li id l bl Long acting, long half life (15 60 hrs) Diffuses into multiple body tissue Once daily dosing schedule
Methadone
Methadone (cont) Methadone (cont) Relapse Relapse rates a function of: rates a function of: Dose of medication Length of time in treatment h f i i Polydrug use Policies of program
Buprenorphine Schedule III Drug Schedule III Drug Treatment use since 2002 (DATA 200) Partial agonist at the mu receptor Partial agonist at the mu receptor Long half life (24 60 hrs) S i Semi synthetic drug th ti d Sublingual administration Prescriber regulations Ceiling Effect of 32mg dose
Buprenorphine
Buprenorphine (cont) Buprenorphine (cont) Suboxone Suboxone formulations include naloxone formulations include naloxone in a in a 4:1 ratio to deter diversion for IV use Buprenorphine 8mg:naloxone 2mg Buprenorphine 8mg:naloxone 2mg Buprenorphine 2mg:naloxone 0.5mg Effectiveness questioned Subs have a definite street market and value Programs evolving to address psychosocial needs of patients needs of patients
Buprenorphine Treatment Buprenorphine Treatment The induction phase The induction phase is the medically monitored is the medically monitored startup of buprenorphine therapy. Buprenorphine for induction therapy is administered when an opioid addicted individual has abstained from using opioids ddi t d i di id l h b t i df i i id for 12 24 hours and is in the early stages of opioid p y g withdrawal. If the patient is not in the early stages of withdrawal (i.e., if he or she has other opioids in the bloodstream), then the buprenorphine dose could precipitate acute withdrawal precipitate acute withdrawal.
Buprenorphine Treatment Buprenorphine Treatment The stabilization phase The stabilization phase has begun when a has begun when a patient has discontinued or greatly reduced the use of his or her drug of abuse, no longer has cravings, and is experiencing few or no side effects The and is experiencing few or no side effects. The buprenorphine dose may need to be adjusted during the stabilization phase. Because of the long h lf lif f b half life of buprenorphine it is sometimes possible hi it i ti ibl to switch patients to alternate day dosing once stabilization has been achieved.
Buprenorphine Treatment Buprenorphine Treatment The maintenance phase The maintenance phase is reached is reached when the patient is doing well on a steady dose of buprenorphine (or dose of buprenorphine (or buprenorphine/naloxone). The length of time of the maintenance phase is individualized for of the maintenance phase is individualized for each patient and may be indefinite.
If you are interested in learning more about buprenorphine both as a treatment and detoxification medication, IRETA is offering a free online learning opportunity for the next month via the online learning portal at ireta.org.
There There you will be able to access two separate you will be able to access two separate and distinct courses Buprenorphine Buprenorphine Treatment: A Training for Treatment: A Training for Multidisciplinary Addiction Professionals "Short term Opioid Withdrawal Using "Sh O i id Wi hd lu i Buprenorphine."
The The online course is completely online course is completely optional June 27, 2012 through July 31, 2012 Free CEUs available F CEU il bl Thank You!